Estrogen Signaling and Synaptogenesis in Hippocampus: The Role of BDNF

Summary

Principal Investigator: Joanna Spencer
Affiliation: Cornell University
Country: USA
Abstract: The long-term goal of the proposed research is to elucidate the mechanisms by which estradiol enhances hippocampal dendritic spine and synapse density and performance of hippocampus-dependent behaviors in female rodents. This proposal addresses the hypothesis that the neurotrophin, brain-derived neurotrophic factor (BDNF), mediates estradiol's actions in the hippocampus. In the first specific aim, I will to characterize the response of the mouse hippocampus to physiologic levels of ovarian hormones, using endpoints previously demonstrated to be increased by estradiol in vitro and/or in vivo rat hippocampus: activation of the mediator of protein translation Akt, activation of the mediator of actin depolymerization LIMK, and expression of the presynaptic vesicle protein synaptophysin. To do this, I will use quantitative immunocytochemistry to examine these endpoints in the mouse hippocampus at high- and low- estradiol phases of the mouse estrous cycle. In the second specific aim, I will determine whether BDNF mediates the effects of ovarian hormones on these endpoints using a mouse model of BDNF deficiency. Using the same quantitative immunocytochemical techniques as in the first aim, I will determine whether the effects of ovarian hormones on the above endpoints are preserved in BDNF-deficient mice compared to wild-type mice. Finally, in the third specific aim, I will determine whether BDNF is important for the effects of ovarian hormones on hippocampal function. To assess the contribution of BDNF to previously reported estrus cycle fluctuations in hippocampus-dependent memory, object placement memory will be performed on wild-type mice and BDNF-deficient mice at high- and low- estradiol phases of the estrus cycle. The influence of estrogens on mental health in women is suggested by gender differences in susceptibility to mental disorders, short-term modulation of mood and cognition by ovarian hormones, and increased risk of depression and cognitive decline after menopause. The proposed studies will investigate the effects of ovarian hormones on the female mouse hippocampus, a part of the brain implicated in psychiatric disorders including depression and dementia. The studies will examine the role of the BDNF molecule in the effects of ovarian hormones, as this molecule has previously been linked to psychiatric disorders including depression. The findings will reveal possible mechanisms by which natural and pharmacological ovarian hormones modulate brain function, influencing susceptibility to psychiatric disorders and dementia across the menstrual cycle and lifespan.
Funding Period: 2007-09-20 - 2010-09-19
more information: NIH RePORT

Top Publications

  1. pmc Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway
    Tracey A Van Kempen
    Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States Electronic address
    Neurosci Lett 552:66-70. 2013
  2. pmc BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function
    Joanna L Spencer
    Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:4395-400. 2010
  3. pmc Cellular and subcellular localization of estrogen and progestin receptor immunoreactivities in the mouse hippocampus
    Katherine L Mitterling
    Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, USA
    J Comp Neurol 518:2729-43. 2010
  4. pmc Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage
    Joanna L Spencer-Segal
    Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10021, USA
    J Neurosci 31:6780-90. 2011
  5. pmc Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation
    J L Spencer-Segal
    Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA
    Neuroscience 202:131-46. 2012
  6. pmc Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice
    Kevin G Bath
    Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA
    Biol Psychiatry 72:499-504. 2012
  7. pmc Estrous cycle regulates activation of hippocampal Akt, LIM kinase, and neurotrophin receptors in C57BL/6 mice
    J L Spencer
    Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA
    Neuroscience 155:1106-19. 2008

Scientific Experts

  • Joanna L Spencer
  • Joanna L Spencer-Segal
  • Bruce S McEwen
  • Kevin G Bath
  • Elizabeth M Waters
  • Teresa A Milner
  • Tracey A Van Kempen
  • J L Spencer-Segal
  • Katherine L Mitterling
  • Mumeko C Tsuda
  • Sana Kahlid
  • Andreina D Gonzalez
  • Sonoko Ogawa
  • E M Waters
  • T A Milner
  • S Ogawa
  • B S McEwen
  • R D Romeo
  • L Mattei
  • M C Tsuda
  • Margaret Altemus
  • Jocelyn Chuang
  • Dima Amso
  • Francis S Lee
  • Moses V Chao
  • Katharine McCarthy
  • Noelle Dziedzic
  • Sushila Shenoy

Detail Information

Publications7

  1. pmc Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway
    Tracey A Van Kempen
    Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States Electronic address
    Neurosci Lett 552:66-70. 2013
    ..This may be due to species-specific differences in the mossy fiber pathway. However, in the mouse, DYN levels are regulated by exogenous EB in the absence of ERα possibly via an ERβ-mediated pathway requiring new gene transcription...
  2. pmc BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function
    Joanna L Spencer
    Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:4395-400. 2010
    ..The variant BDNF Val66Met should therefore be considered as a strong candidate for mediating genetic differences in ovarian steroid-related behavioral changes and disorders...
  3. pmc Cellular and subcellular localization of estrogen and progestin receptor immunoreactivities in the mouse hippocampus
    Katherine L Mitterling
    Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, USA
    J Comp Neurol 518:2729-43. 2010
    ....
  4. pmc Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage
    Joanna L Spencer-Segal
    Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10021, USA
    J Neurosci 31:6780-90. 2011
    ..These findings suggest that presynaptic TrkB is positioned to modulate estradiol-mediated and BDNF-dependent synaptic plasticity. Furthermore, they suggest a novel role for TrkB in microglial function in the neuroimmune system...
  5. pmc Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation
    J L Spencer-Segal
    Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA
    Neuroscience 202:131-46. 2012
    ..By further delineating these mechanisms, we will better understand and predict the effects of endogenous and exogenous ovarian steroids on mood, cognition, and other hippocampal-dependent behaviors...
  6. pmc Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice
    Kevin G Bath
    Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA
    Biol Psychiatry 72:499-504. 2012
    ..Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question...
  7. pmc Estrous cycle regulates activation of hippocampal Akt, LIM kinase, and neurotrophin receptors in C57BL/6 mice
    J L Spencer
    Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA
    Neuroscience 155:1106-19. 2008
    ..The findings suggest that endogenous estradiol and progesterone produced by the ovaries modulate specific signaling pathways governing actin remodeling, cell excitability, and synapse formation...